Update on Pharmacologic Treatments for Alcoholism

Transcription

1 Update on Pharmacologic Treatments for Alcoholism Michel A. Sucher, MD Presentation to California Society of Toxicologists Phoenix, AZ June 8, 2007 Disclosure Michel A. Sucher,, MD is on the Speakers Bureaus of the following pharmaceutical companies: Alkermes Cephalon Forest Pharmaceuticals Disclosure Dr. Sucher may discuss the use of medications for off label usage. Dr. Sucher will note when use of medication is off label. Goals Know what areas of the brain are involved in alcoholism. Understand the mechanisms of action of the three FDA approved medications for treating alcohol dependence. Be able to distinguish the various pharmachotherapeutic choices for treating alcohol dependence in combination with psychosocial interventions.

2 Prevalence of Alcohol Abuse and Dependence $1,253 (1%) Costs of Alcohol Abuse Total Cost: $184.6 Billion $10,085 (5%) $24,093 (13%) $7,466 (4%) $15,963 (9%) $2,909 (2%) $86,368 (47%) $36,499 (20%) Cost in millions of US dollars. FAS = fetal alcohol syndrome. Specialty Alcohol Services Medical Consequences (except FAS ) Medical Consequences of FAS Lost Future Earnings Due to Premature Deaths Lost Earnings Due to Alcohol-Related Illness Lost Earnings Due to FAS Lost Earnings Due to Crime/Victims Crashes, Fires, Criminal Justice, etc Source: Harwood, H. Report prepared by the Lewin Group for the National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health, NIH Publication No Rockville, Md. Available at: Accessed March 1, Societal Costs of Alcohol Abuse Alcohol-related problems cost every man, woman and child in American roughly $683 (in 1998 dollars) each year. The cost of alcohol problems includes: lost productivity health care expenditures to treat alcoholism and other medical consequences alcohol-related motor vehicle crashes alcohol-related crime Sources: McGinnis, J.M., & Foege, W.H., Actual causes of death in the United States, Journal of the American Medical Association 270(18): , Societal Costs of Alcohol Abuse Almost half (45 percent) of the cost of alcohol problems is borne by problem drinkers and their households. Society also pays for the negative effects of alcohol use: federal government pays 20 percent state and local governments pay 18 percent private insurers pay 10 percent the victims of alcohol-related crime and the non-drinking victims of motor vehicle crashes pay 6 percent. Sources: McGinnis, J.M., & Foege, W.H., Actual causes of death in the United States, Journal of the American Medical Association 270(18): , 1993.

3 Societal Costs of Alcohol Abuse About three out of every 10 Americans will be involved in an alcohol-related traffic crash during their lifetime. 40% of people killed in alcohol-related traffic crashes were people other than the drinking driver. Binge drinkers are 30 times more likely to drive while impaired than those who do not binge. 75% of drivers convicted of driving while impaired are either problem drinkers or people with alcoholism Sources: McGinnis, J.M., & Foege, W.H., Actual causes of death in the United States, Journal of the American Medical Association 270(18): , Societal Costs of Alcohol Abuse The majority of 8th and 10th graders report it is easier to buy alcohol than cigarettes in their communities. Adults who purchase alcohol for minors and businesses that sell alcohol to minors are rarely prosecuted for violations of minimum drinking age laws. Sources: McGinnis, J.M., & Foege, W.H., Actual causes of death in the United States, Journal of the American Medical Association 270(18): , Societal Costs of Alcohol Abuse For every 1,000 minors arrested for alcohol possession, criminal penalties are faced by only 130 of the businesses and only 88 of the adults. Violence occurs more often in neighborhoods where alcohol is widely available than in those where it is not. 25% of all children are raised in families of alcoholic at least one parent Sources: McGinnis, J.M., & Foege, W.H., Actual causes of death in the United States, Journal of the American Medical Association 270(18): , Lifetime Probability of Treatment/Help Seeking for Drug Abuse/Dependence Cumulative Lifetime Probability of Treatment Contact Abuse Dependence Years Since Onset of Drug Use Disorder

4 Prevalence of Alcohol Use NIAAA National Epidemiologic Survey on Alcohol and Related Conditions Any Alcohol Disorder 9.7 Alcohol Abuse 7.9 Alcohol Dependence NIAAA = National Institute on Alcohol Abuse and Alcoholism. Source: Grant BF, et al. Arch Gen Psychiatry. 2004;61: Seeking Treatment Receiving Medication Million Limbic Region Role: Drive Generation Intervention: Pharmacotherapy Comprehensive Alcohol Dependence Treatment Cortex Role: Decision Making Intervention: Counseling Alcohol Addiction Alcohol Addiction Arcuate Nucleus

5 Understanding Alcohol Addiction DSM IV-R R Abuse (Need 1) Role Impairment (e.g. failed work or home obligations) Hazardous use (e.g. Driving while intoxicated) Legal problems related to alcohol use Social or interpersonal problems due to alcohol Understanding Alcohol Addiction DSM IV-R R Dependence (Need 3 of 7 in 12 months) 1. Tolerance 2. Withdrawal 3. Substance is taken in larger amounts or over a longer period than was intended 4. Persistent desire or unsuccessful efforts to cut down or control substance use 5. Important social, occupational, or recreational activities are given up or reduced because of substance use 6. Continuation despite adverse consequences 7. Substance use continued despite having a persistent or recurrent physical or psychological problem has been caused or exacerbated by the substance Defining the Standard Drink A standard drink = 14 g ethanol 12 oz of regular beer or cooler (5% alcohol) 5 oz of table wine (12% alcohol) 1.5 oz of hard liquor (40% alcohol, 80 proof) The average person metabolizes about 1 standard drink per hour 12 oz, beer or cooler 8-99 oz, 5 oz, malt liquor table wine 8.5 oz shown in a 12-oz glass that, if full, would hold about 1.5 standard drinks of malt liquor 3-44 oz, fortified wine (such as sherry or port) 3.5 oz shown 2-33 oz, cordial, liqueur, or aperitif 2.5 oz shown 1.5 oz, 1.5 oz, brandy spirits (a single jigger) (a single jigger of 80-proof gin, vodka, whiskey, etc) shown straight and in a highball glass with ice to show level before adding mixer Understanding Alcohol Addiction What is Addiction? Neurochemical Disorder It s s all in the brain Genetic Transmission Chromosome 2, 5, 7, 11, 15 Chronic Disease But not always Long Term Treatment But not always 12 oz 8.5 oz 5 oz 3.5 oz 2.5 oz 1.5 oz 1.5 oz Source: National Institute on Alcohol Abuse and Alcoholism. Bethesda, Md: NIAAA; NIH Publication No

6 Screening for Alcohol Use Disorders Identify individuals with potential alcohol problems Initiate psychotherapy and pharmacotherapy Provide advice for further treatment options Monitor response to therapy Promote relapse prevention Source: Fiellin DA, et al. Arch Intern Med. 2000;160: Biologic Marker Gamma- glutamyl transferase Carbohydrate- deficient transferrin Mean corpuscular volume Screening Instruments: Clinical Laboratory Tests A blood protein that increases with heavy alcohol consumption Elevated levels after 4 to 8 weeks of chronic drinking of 4 or more m drinks/day Useful for monitoring abstinence as it usually takes 4 to 5 weeks s of abstinence for GGT levels to return to normal range Likelihood of false positive (nonalcoholic liver disease) A blood protein that increases with heavy alcohol consumption Elevated after 1 to 2 weeks of excessive drinking Low sensitivity in women and adolescents Index of red blood cell size Clinical Significance Increases with excessive alcohol intake after 4 to 8 weeks Detects evidence of earlier drinking prior to a long period of abstinence, a making it a poor indicator of recovery in alcoholics Source: National Institute on Alcohol Abuse and Alcoholism. Bethesda, Md: NIAAA; Alcohol Alert, No. 56. Screening Instruments: Clinical Laboratory Tests Biological Marker Ethyl Glucuronide Clinical Significance Tested primarily in urine but detectable in blood as well Minor metabolite of ethyl alcohol Detects single drink for hours Detects significant alcohol ingestion for days False positives from environmental contaminants Screening Instruments Self-Report Questionnaires and Structured Interviews: CAGE questionnaire Alcohol Use Disorders Identification Test (AUDIT) Michigan Alcoholism Screening Test (MAST) Brief MAST (BMAST) TWEAK questionnaire

7 Screening Instruments: Brief Screening Questionnaires Alcohol Dependence Screening Tool: CAGE Questionnaire Screening Tool Questions (Scoring) Cutoff Value Intended Setting Sensitivity Have you ever felt you should CUT down on your drinking? CAGE 4 (1 point each) 2 Clinical % 100% Have people ANNOYED you by criticizing your drinking? AUDIT 10 (0-4 4 points each) 8 Clinical (adolescents) 38-94% Have you ever felt bad or GUILTY about your drinking? BMAST TWEAK 10 (0-4 4 points each) 5 (0-2 2 points each) 6 2 Clinical and nonclinical Clinical (pregnant women) 30-78% 70-90% Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (ie, EYE- OPENER)? Indicates questionnaires that can be self-administered. Source: Cherpitel CJ. Alcohol Health Res World. 1997;21: Source: Cherpitel CJ. Alcohol Health Res World. 1997;21: Alcohol Dependence Screening Tool: AUDIT Questionnaire Alcohol Dependence Screening Tool: BMAST Questionnaire 1. How often do you have a drink containing alcohol? 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 3. How often do you have 6 or more drinks on 1 occasion? 4. How often during the past year have you found that you were not able to stop drinking once you had started? 5. How often during the past year have you failed to do what was normally expected of you because of drinking? 6. How often during the past year have you needed a first drink in the morning to get yourself going after a heavy drinking session? 7. How often during the past year have you had a feeling of guilt or remorse after drinking? 8. How often during the past year have you been unable to remember what happened the night before because you had been drinking? 9. Have you or has someone else been injured as a result of your drinking? 10. Has a relative, friend, or a doctor or other health care worker been concerned about your drinking or suggested you cut down? 1. Do you feel you are a normal drinker? 2. Do friends or relatives think you are a normal drinker? 3. Have you ever attended a meeting of Alcoholics Anonymous (AA)? 4. Have you ever lost friends or girlfriends/boyfriends because of drinking? 5. Have you ever gotten into trouble at work because of drinking? 6. Have you ever neglected your obligations, your family, or your work w for two or more days in a row because you were drinking? 7. Have you ever had delirium tremens (DTs), severe shaking, heard voices, or seen things that weren t t there after heavy drinking? 8. Have you ever gone to anyone for help about your drinking? 9. Have you ever been in a hospital because of drinking? 10. Have you ever been arrested for drunk driving or driving after drinking? Source: Saunders JB, et al. Addiction. 1993;88: Source: Pokorny AD, et al. Am J Psychiatry. 1972;129:

8 Alcohol Dependence Screening Tool: TWEAK Questionnaire TOLERANCE: How many drinks can you hold? Have close friends or relatives WORRIED or complained about your drinking in the past year? EYE-OPENER: Do you sometimes take a drink in the morning when you first get up? AMNESIA: Has a friend or family member ever told you about things you said or did while you were drinking that you could not remember? Screening Instruments for Alcoholism These tools are useful in all clinical settings but are particularly useful in: Primary Care Emergency Departments and Urgent Care Centers Trauma Cases Inpatient Hospitalizations where the patients condition may be related to alcohol Do you sometimes feel the need to C(K)UT drinking? DOWN on your Source: Cherpitel CJ. Alcohol Health Res World. 1997;21: Alcohol Pharmacotherapy Disulfiram (Antabuse) Approved for use in the US in 1951 Inhibits aldehyde DH Leads to flushing, nausea, dizziness and headache Hepatotoxic Patients frequently challenge themselves Death can result Alcohol Metabolism Ethanol Alcohol DH Acetaldehyde Aldehyde DH Acetate

9 Alcohol Pharmacotherapy Ondansetron (Zofran) 5 HT-3 3 antagonist 5-HT3 receptors in the VTA regulate alcohol drinking and the reinforcing effects of alcohol May be useful in Early Onset Alcoholism (EOA) Off label use Expensive Alcohol Pharmacotherapy Topiramate (Topamax) A glutamate antagonist A GABA A agonist May reduce quantity of drinking and improve patient out comes Reduces binges Can cause glaucoma and renal stones Off label Alcohol Pharmacotherapy VIVITROL and Brain Reward Pathways Naltrexone (Vivitrol, Revia) Opiate receptor antagonist May block some acute intoxicating effects of alcohol Blocks dopamine reward pathway Decreases alcohol consumption Long half life May cause liver damage Ventral Tegmental Area Arcuate Nucleus Nucleus Accumbens Dopamine Opioid Peptides VIVITROL

10 VIVITROL Microspheres Plasma Concentrations Hydration Diffusion Erosion Elimination: polymer eventually metabolized and eliminated as CO 2 and H 2 O Dean RL. Front Biosci. 2005;10: Data on File. Alkermes, Inc. Dean RL. Front Biosci Jan 1;10: Dunbar JL, et al. Alc Clin Exp Res. 2006;30: Data on File, Alkermes, Inc. VIVITROL Prolonged Abstinence VIVITROL Significantly Reduced Drinking Days Patients abstinent for 7 days prior to treatment initiation Data on file. Alkermes, Inc. Patients abstinent for 7 days prior to treatment initiation Data on file. Alkermes, Inc.

11 VIVITROL Significantly Reduced Heavy Drinking Days Subjects With Nausea by Month Mild in the vast majority of reports Occurred only in the first month in the majority of cases Median duration of a few days Trial dropout rate attributed to nausea was 2% Patients abstinent for 7 days prior to treatment initiation Data on file. Alkermes, Inc. Data on File. Alkermes, Inc. Injection Site Location VIVITROL should be injected into the dorsogluteal site Upper outer quadrant of the buttock Alternate buttocks with each monthly injection Alcohol Pharmacotherapy Acamprosate (Campral) Glutamate antagonist Pre-,, post- and intersynaptic effects Blocks compulsive behavior associated with alcohol consumption Decreases alcohol consumption Long half life Low bioavailability No liver damage

12 Acamprosate International Double-Blind Trials: Rates of Complete Abstinence months 6 months 12 months ACAMP Placebo Percentage of Patients Completely Abstinent 10 0 Namkoong, 2003 Lhuintre, 1985 Roussaux, 1996 Pelc, 1997 Baltieri, 2003 Kiefer, 2003 Pelc, 1992 Ladewig, 1993 Geerlings, 1997 Poldrugo, 1997 Chick, 2000 Tempesta, 2000 Gual, 2001 Barrias, 1997 Paille, 1995 Sass, 1996 Whitworth, 1996 Besson, 1998 P<.05 Adapted from: Mason BJ. Expert Opin Pharmacother. 2005;6: Additional source: Kiefer F, et al. Arch Gen Psychiatry. 2003;60:92-99.

13 Efficacy of Acamprosate in Regaining Abstinence Relapsed Patients Who Regained Abstinence (Pooled Analysis of 13-,, 48-,, and 52-Week Pivotal Studies) Percentage of Relapsed Patients n=319 P< % n=268 Relapse in all studies was considered any consumption of alcohol and was assessed by both patient reports and objective measures. All study arms included psychosocial support. 5% ACAMP Placebo Sources: Schneider E, et al. Presented at: American Academy of Addiction Psychiatry 16th Annual Meeting and Symposium; Dec 8-11, 2005; Scottsdale, Ariz. Data on file, Forest Laboratories, Inc.

14 Efficacy of Acamprosate in Reducing the Severity of Relapse Median Number of Drinks per Drinking Day Number of Drinks per Drinking Day (Analysis of 15 Placebo-Controlled Studies) ACAMP 4.8 Placebo Day 30 Day 90 Day 180 Day 360 P<.05 n=983 n=927 n=651 n=244 Source: Chick J, et al. J Psychopharmacol. 2003;17: Efficacy of Acamprosate in Reducing the Severity of Relapse P<.05 Median Number of Drinking Days per Week Frequency of Drinking Days per Week (Analysis of 15 Placebo-Controlled Studies) 4.2 ACAMP 3.8 Placebo Day 30 Day 90 Day 180 Day 360 n=983 n=927 n=651 n=244 Source: Chick J, et al. J Psychopharmacol. 2003;17: Dosage and Administration A Campral Dose Pak is available. It includes a 30-day supply along with patient education materials A stock bottle with a 30-day supply is also available Combination Pharmacotherapy May use the agents we discussed alone or in combination No contraindications for concomitant use of disulfiram, naltrexone or acamprosate Many patients benefit from combination therapy Source: Campral package insert. Forest Pharmaceuticals, Inc.

15 Pharmacotherapy: Who Needs It? NIAAA Clinician Guidelines All approved drugs have been shown to be effective adjuncts to the treatment of alcohol dependence. Thus, consider adding medication whenever you are treating someone with active alcohol dependence or someone who has stopped drinking in the past few months but is experiencing problems such as craving or slips. NIAAA NIH Government Publications. Helping Patients Who Drink Too Much: A Clinician s Guide Edition. Available at Accessed September 7, Clinical Guidelines Pharmacologic Treatments should always include psychosocial treatments in addition to medication Alcoholics Anonymous Counseling and/or therapy Outpatient Treatment Inpatient or Residential Treatment Medication Adherence Patients who adhere to their medication regimen do better in terms of: Continuous abstinence Reduced drinking and heavy drinking days Risk of relapse Compliance with psychosocial treatment modalities

16 Summary Thanks for your time and attention Questions???